FR2848856A1 - Production of a material useful for making bone implants and prostheses by molding a mixture of a binder and calcium and phosphorus compounds comprises cleaning the surface of the molded piece - Google Patents

Abstract

Production of a material for medical or veterinary use comprises mixing a binder with one or more calcium and phosphorus compounds, molding the mixture, cleaning the surface of the molded piece and aseptically packaging the product. An Independent claim is also included for a material as above.

Description

The present invention relates to an original material which can be used

in the

  The medical or veterinary field, in particular but not exclusively for the production of endosseous implants, in particular dental, or for the production of bone prostheses The invention also relates to the process for obtaining this material, as well as its applications.

  Many types of materials, metallic or plastic, are used in the medical or veterinary field for the replacement of biological structures (bone in particular) or for the fixation of functional organs (dental implants or others). The choice of material is made according to its intrinsic structural characteristics and also according to its biocompatibility in terms of tolerance or, what is better, in terms of biological acceptance.

  Document FR-A-2 722 694 describes a molded material for producing endosseous implants or bone prostheses, consisting of a thermoplastic polymer (in particular poly (etheretherketone), also called PEEK) comprising calcium hydroxyapatite, tricalcium phosphate, orthophosphoric acid and a Ti O 2 type zeolite.

  Despite the encouraging results obtained with this type of material, it turns out that the results in terms of biological integration are not entirely satisfactory. The present invention provides a new material derived from that described in the aforementioned document FR-A-2 722 694, which combines good general mechanical qualities and very good biocompatibility in terms of biological acceptance, capable of allowing efficient use. both in the medical and veterinary fields.

  The corresponding material is in the form of a molded part consisting of a biocompatible binder containing one or more compounds providing calcium and phosphorus, which molded part has undergone a surface pickling operation.

  This pickling ensures the surface setting and therefore the surface access of the elements added to the binder, in particular calcium and phosphorus; this allows the creation or at least of promoting the creation of ionic bonds between these added elements and the surrounding chemical elements, mineral or organic, after biological implantation of the piece of material And in the presence of added absorbable elements, once these disappeared elements, the tissues, the biological cells or the surrounding chemical elements can find a place of integration in the material. This feature makes it possible to improve adhesion and cell colonization in order to ensure good biological acceptance of the graft type and good biocompatibility of the implant.

  The biocompatible binder is chosen according to its physical characteristics 5 after shaping, in particular by an injection molding operation. For example, a thermoplastic polymer of the poly (etheretherketone) type, a polyether ketone, a polyether block amides, a polysulfone, a polytetrafluoroethylene or a polyimide; it is also possible to use a natural polymer, in particular of the cellulose type. This polymer may or may not be absorbable.

  Given its high Young modulus and its interesting structural characteristics which approximate those of bone, poly (etheretherketone) (PEEK) is preferably used. PEEK is a semi-crystalline polymer formed from a linear aromatic chain based on the repetition of the following units: ocoon The characteristics of this polymer are developed in the commercial brochure published in 1992 by the company ICI MATERIALS: "Victrex PEEK, the high temperature engineering thermoplastic-properties and processing".

  The calcium and phosphorus supplies are advantageously made by calcium phosphates derived for example from tricalcium phosphate (Ca 3 (PO 4) 2), dicalcium or monetite phosphate (Ca H PO 4), calcium hydroxyapatite ( (Ca 5 (PO 4) 3 OH) or (Ca 10 (PO 4) 6 H 20)), with a stoichiometric formulation or not, or of products containing them.

  The presence of calcium phosphates allows the material to approach the natural composition of the bone in order to strengthen the biocompatibility. Products containing calcium phosphates which are at least partially absorbable are preferably used. In particular, calcium hydroxyapatite is a component found in bone. It can advantageously be used in its non-stoichiometric form, because it is therefore slightly absorbable, which is advantageous for integration. tissue. *, 2848856 Dicalcium or tricalcium phosphate has the advantage of being inexpensive and of being one of the basic biological components for the formation of calcium hydroxyapatite; it is also absorbable and also has a healing function.

  We can still use these different calcium phosphate mixtures.

  In addition to the supply of calcium phosphates, the molded material in accordance with the invention may include orthophosphoric acid (H 3 (P 04)) Orthophosphoric acid in kind is prescribed as a calcium fixer and as an acidifier; it is also a fundamental constituent of nucleotides which are the basic units of nucleic acids, which participate in the constitution of the nucleus of living cells.

  In addition, the material according to the invention is advantageously charged with one or more compounds making it possible to create or promote the electrostatic bonds with the surrounding medium. This or these charges can be chosen from zeolites and / or certain oxides; it is in particular possible to envisage using ceramics such as titanium dioxide (Ti O 2), zirconium dioxide (Zr O 2), aluminum oxide (AI 203) or silicon dioxide (Si O 2).

  The charges in question are electrostatic compounds which allow an ion bonding function; they also have a high molar mass and they contribute to improving the radiopacity of the material.

  The material according to the invention is shaped by molding, injection or extrusion type, of a homogeneous mixture of constituents. The molding material and conditions are adapted to this mixture, and in particular to the nature of the binder used.

  To preserve a moldable material having sufficient strength and resistance, the polymeric binder represents at least 65%, and preferably 65% to 90%, by weight of the final material.

  On the other hand, to provide sufficient chemical elements intended to promote biological integration, the complementary components (tricalcium phosphate and / or dicalcium phosphate and / or calcium hydroxyapatite, optionally associated with at least one compound of the type zeolite or oxide for example, intended to improve electrostaticity and radiopacity, and to orthophosphoric acid) represent between 10 and 35% by weight of the final material.

  A good compromise, in particular in terms of mechanical characteristics, corresponds substantially to 80% by weight of polymeric binder and 20% by weight of complementary component (s). The invention also relates to the process for obtaining this material. The corresponding process consists in: homogeneously mixing a biocompatible moldable binder with one or more compounds providing calcium and phosphate, subjecting the mixture obtained to an operation of molding, to perform one or more operations of surface stripping and decontamination of the molded part, to aseptically condition said decontaminated part.

  The surface pickling operation is advantageously carried out by means of at least one bath in a solution, in particular of pickling product, subjected to ultrasound. Preferably, the surface pickling and decontamination operations are carried out by passing the molded part through successive baths of hydrochloric or sulfuric acid, acetone, hydrogen peroxide, sodium hypochloride and product ( s) disinfectants, subjected to ultrasound, separated by rinsing operations with water or passing through water baths subjected to ultrasound.

  Examples Basic mixtures are produced from poly (etheretherketone) (PEEK), tricalcium phosphate (Ca 3 (PO 4) 2), and titanium dioxide (Ti O 2).

  PEEK comes in the form of a powder or granules (size: about 100 microns), distributed by the Company Victrex Europa Gmb H, Hauptstr 11 D-65719 HOFHEIM Germany.

  Tricalcium phosphate is available in powder form (grains of size close to 200 microns); it is for example marketed by S A Coopération Pharmaceutique Française, 77020 MELUN France.

  Titanium oxide is also available in the form of a powder distributed by S A Coopération Pharmaceutique Française, 77020 MELUN France; a) Proportions Some examples of possible compositions are indicated below: Mixture 1 (10% of fillers) Mixture 2 (20% of fillers) -PEEK: 90% by weight -PEEK: 80% by weight Ca 3 (PO 4 ) 2: 5% by weight Ca 3 (PO 4) 2: 10% by weight Ti O 2: 5% by weight Ti O 2: 10% by weight Melanqe 3 (30% of fillers) Mixture 4 -PEEK: 70% by weight -PEEK: 65% by weight Ca 3 (PO 4) 2: 15% by weight Ca 3 (PO 4) 2: 17.5% by weight Ti O 2: 15% by weight Ti O 2: 17.5 % by weight b) Mixing The constituents of each mixture are placed in a turbine mixer until perfect homogenization is obtained.

  c) Drying Each homogeneous mixture obtained is dried in an air circulation oven for 3 hours at 150 C.

  d) Molding The molding operation is carried out on a KRAUSSMAFFEI type injection press, Model 90-340-32, Société KRAUSS MAFFEI FRANCE, 92632 GENNEVILLIERS FRANCE.

  The conditions of preparation of the material and the conditions of molding of the mixture correspond to the commercial brochure "ICI MATERIALS" indicated above15.

  PEEK being a semi-crystalline thermoplastic, it is necessary to heat the mold to a temperature at least higher than that of its glass transition (140 C) Otherwise the surface quality of the molded parts would be affected Indeed, the surface veil would be in amorphous phase and the heart in crystalline phase; if the mold 20 was too cold, the parts could even have a completely amorphous character and the mechanical characteristics would drop severely.

  The thermoregulation of the mold is ensured by an oil heater making it possible to maintain it at a temperature of the order of 160 C. Insulation means limit thermal dispersions and preserve the peripheral organs of the injection molding machine These means can be present in the form of insulating plates formed from a complex of glass fibers.

  For mass injections, a vibrator will advantageously be attached to the hopper to promote the flow of the mixture.

  Generally, the molding is carried out at a temperature of the order of 340 to 400 C and at an injection pressure close to 70 to 140 M Pa.

  The mold can be shaped as a function of the part which it is desired to obtain, for example for the production of a bone prosthesis, in particular for orthopedic applications. It is also possible to obtain a block of material which is then cut or machined. depending on the desired shape, for bone filling or an implant, dental type for example.

  e) Surface pickling decontamination Once the molded material obtained, it is subjected to surface pickling and decontamination operations, before aseptic conditioning.

  These operations are advantageously carried out initially by passing the molded material through different baths of products subjected to ultrasound; each product used can act as a surface stripper or disinfectant, or both.

  In any event, the product or products ensuring the surface stripping function are adapted, in conjunction with ultrasound, so as to show on the surface 10 in particular phosphorus and calcium (in the form of calcium phosphate), and the titanium dioxide The accessibility on the surface of calcium phosphate promotes exchanges with the environment and the electrostatic attachment of certain chemical elements present in the biological environment of the material after implantation; these exchanges and / or these electrostatic adhesions induce cellular penetration into the implanted material. Also, the presence on the surface of titanium dioxide potentiates these exchanges and the presence of electrostatic bonds.

  In addition, since calcium phosphate is at least partially absorbable, its disappearance after implantation of the material allows the creation of cavities or a network of cavities, promoting cell penetration of the surrounding tissues.

  The products used for these pickling and decontamination operations can be hydrochloric acid (HCl, for example at 30%) or sulfuric acid (H 2 SO 4, for example at 30%), acetone (C 3 H 60), hydrogen peroxide (H 202, at 110 vol or 30% for example), and / or sodium hypochloride (Na Clo) preferably used in combination Advantageously, complementary baths of products are used. 25 purely disinfectant function, such as Gigasept (registered trademark) or Lysetol (registered trademark).

  The corresponding protocol for implementing these pickling / decontamination operations may consist in placing the implant in the following successive baths subjected to ultrasound: 30 HCI 30%: 20 min H 20: 10 min (or rinsing) acetone: 20 min H 20: 10 min (or rinse) H 202 30%: 20 min Nacl O: 20 min H 20:10 min (or rinse) Gigasept 12%: 60 min H 20 Ppi: 20 min (or rinse) The implant is inserted in a sterilization sheath for its passage in autoclave; it then undergoes a sterilization cycle at a temperature of the order of 5 135 C for 10 minutes, under a pressure of the order of 2150 mbar This sterilization operation by autoclave contributes to the surface pickling function; it can be combined with treatment with ethylene oxide or with gamma rays. f) Results An analysis by scanning electron microscope (SEM) shows that the pickling / decontamination and sterilization operations favor the appearance of calcium phosphates on the surface. These calcium phosphates emerge by micropores and crystallize.

  After implantation, the surface analysis shows the presence of holes and crevices on the surface of the material, and also the presence of carbon, oxygen and nitrogen, while there is little calcium and phosphorus in relation at the initial integrated concentrations.

  This tends to show the partial disappearance of the calcium phosphate particles on the surface, and the colonization of the holes and crevices by surrounding biological materials, sign of a graft-type biological acceptance.

  A clinical analysis from implanted implants shows that the material in question develops on contact with a bone cortex as a consequence of the physical and atomic characteristics of the material.

  This is a real graft principle; these results demonstrate the clinical reality of an integration of the material into the surrounding tissue.

Claims (16)

  1. Material for medical or veterinary use, in particular for the production of endosseous implants, in particular dental implants, or for the production of bone prostheses, which material is in the form of a molded part, consisting of a binder biocompatible containing one or more compounds providing calcium and phosphorus, characterized in that it has undergone a surface stripping operation. 2. Material according to claim 1, characterized in that it comprises calcium phosphate as compound providing the supply of calcium and phosphorus, which calcium phosphate is derived from calcium hydroxyapatite and / or dicalcium phosphate or tricalcium.   3. Material according to any one of claims 1 or 2, characterized in that it comprises a binder in the form of a thermoplastic polymer.   4. Material according to claim 3, characterized in that it comprises a binder 15 in the form of a thermoplastic polymer of the kind PEEK (polyetheretherketone) 5. Material according to any one of claims 1 to 4, characterized in that it comprises a binder in the form of a natural polymer of the cellulose type.   6. Material according to any one of claims 1 to 5, characterized in that it comprises a compound of zeolite or oxide type, such as Ti O 2, Si O 2, A 1203 or Zr O 2. 20 7 Material according to l any one of claims 1 to 6, characterized in that it comprises: 90% by weight of polymeric binder, and 35% by weight of complementary component (s) in the form of calcium hydroxyapatite and / or dicalcium or tricalcium phosphate, optionally associated with at least one zeolite or an oxide.   8. Method for obtaining the material for medical or veterinary use according to any one of claims 1 to 7, characterized in that it consists in: homogeneously mixing a biocompatible moldable binder with one or more compounds providing a supply of calcium and phosphorus, 30 subjecting the mixture obtained to a molding operation, carrying out one or more operations of surface etching and decontamination of the molded part, aseptically conditioning said decontaminated part.   9. Method according to claim 8, characterized in that the surface pickling operation is carried out by means of at least one bath in a solution subjected to ultrasound.   10. Method according to claim 9, characterized in that the surface pickling operation is carried out by means of at least one bath of pickling product subjected to ultrasound.   11. The method of claim 10, characterized in that the surface treatment is carried out by passing the molded material through different successive baths subjected to ultrasound.   12. Method according to claim 11, characterized in that the surface treatment is carried out by passing the molded material through at least one acid bath of the hydrochloric acid or sulfuric acid type.   13 Method according to any one of claims 11 or 12, characterized in that the surface treatment is carried out by passing the material through at least one acetone bath.   14. Method according to any one of claims 11 to 13, characterized in that the surface treatment is carried out by passing the material through at least one bath of hydrogen peroxide.   15. Method according to any one of claims 11 to 14, characterized in that the surface treatment is carried out by passing the material through at least one bath of sodium hypochloride.   16. Method according to any one of claims 11 to 15, characterized in that it consists in subjecting the molded part to a decontamination treatment by means of baths carrying out the surface pickling / decontamination treatment, associated with at least one complementary bath of decontaminating product.   17. Method according to any one of claims 8 to 16, characterized in that the surface pickling and decontamination operations are carried out by passing the molded part through successive baths of hydrochloric or sulfuric acid, acetone , hydrogen peroxide, sodium hypochloride and disinfectant product (s), subjected to ultrasound, separated by rinsing operations with water or passage through water baths subjected to ultrasound.   18. Method according to any one of claims 8 to 17, characterized in that it consists in subjecting the molded part to an autoclave sterilization operation after passage through at least one solution bath subjected to ultrasound.   19. Application of the material according to any one of claims 1 to 7, or obtained by the process according to any one of claims 8 to 18, for the production of endosseous implants, in particular dental implants.   20. Application of the material according to any one of claims 1 to 7, or obtained by the method according to any one of claims 8 to 18, for the production of bone prostheses.